The present invention relates to a pyridinol derivative or pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating an inflammatory bowel disease containing the derivative or salt as an active ingredient.
An inflammatory bowel disease (IBD) is classified into two types of diseases such as ulcerative colitis and Crohn's disease, which are clinically similar, but different depending on histological opinions, and endoscopic and immunological aspects. It has been known that such IBD is mainly caused by the activation of inflammatory cells.
Continuous or improper activation in a bowel immune system plays a pivotal role for pathological physiology of chronic mucosal inflammation, and particularly, the infiltration of neutrophils, macrophages, lymphocytes and mast cells results in mucosal destruction and ulcers. Infiltrated and activated neutrophils are the critical cause of active oxygen nitrogen species, and such active species, as cytotoxic materials, induce cellular oxidative stress by a crosslinking protein, a lipid and a nucleic acid and result in epithelial dysfunction and damage.
When an inflammatory disease occurs, various inflammatory cytokines are secreted from the mucosa of the intestinal tract. TNF-α is highly expressed in the colonic lumen and colonic epithelial cells in patients with ulcerative colitis. According to a recent study, TNF-α has been known to play an important role in the pathogenesis of ulcerative colitis. An anti-TNF-α antibody, infliximab, has been known to be effective in treatment of Crohn's disease which had not been previously treated, as well as treatment of furuncles. However, these therapies are costly and, in some patients, cause side effects such as fluid reactions or infectious complications.
Monocyte chemoattractant protein-1 (MCP-1) is a 14-kDa member of the C—C chemokine family which mainly recruits and activates monocytes/macrophages in an inflammatory area. It has been reported that MCP-1 is localized and expressed in colonic epithelial cells and associated with monocyte infiltration in the mucosa of IBD patients. Unlike other chemokines, MCP-1 only binds to CCR2, and thus it has been known that the MCP-1/CCR2 binding is a key modulator for monocyte recruitment and plays an important role in IBD.
In addition, it has been known that, in the mucosa of an IBD patient, interleukin-8 (IL-8) significantly increases and promotes microvascular angiogenesis. As the inflammation becomes severe in the colon, IL-8 expression is increased, and therefore, it has been known that, in animal test models using rodents, an IL-8 specific antibody reduces bowel inflammation. Here, an intracellular Ca2+ change acts as a key factor in IL-8 induction.
As currently used IBD therapeutics, 5-aminosalicylic acid (5-ASA)-based drugs that interrupt the generation of prostaglandins, for example, sulfasalazine, have been used, or steroid immunosuppressants have been used.
Sulfasalazine is prone to side effects or adverse effects such as abdominal fullness, headaches, rashes, liver diseases, leukopenia, agranulocytosis, male infertility, etc. In addition, it is not sure whether sulfasalazine has a sufficient effect of inhibiting recurrence in patients with resected lesions or those with improvement.
Steroid immunosuppressants are adrenocortical steroids, which are recognized for short-term effects, but may not improve long-term prognosis. In addition, there are limitations that should only be used in acute cases in terms of side effects such as induced infectious diseases, secondary adrenal insufficiency, peptic ulcers, diabetes, psychiatric disorders, and steroidal kidney diseases.
In other words, since a reliable oral therapy for IBD has not been developed yet, there is a demand for development of an effective and low-cost oral therapeutic for such a disease.